“Breathing” Hemagglutinin Reveals Cryptic Epitopes for Universal Influenza Vaccine Design

Recent advances in “universal” influenza virus antibodies: the rise of a hidden trimeric interface in hemagglutinin globular head

“…These findings suggest that the HA trimer is dynamic [88][89][90] and that the interface can be opened, perhaps transiently or partially, to expose conserved sites. The "breathing" of the interface of the HA head domain has also been reported [16][17][18]87]. HA0 is the HA precursor protein.…”

“…This interface was previously considered to be hidden but can be exposed according to the recently proposed HA "breathing" theory [16]. Consequently, panels of broadly neutralizing antibodies targeting these epitopes were identified [16][17][18]. In the present work, we review the recent progress on these novel "universal" antibodies and discuss the potential implications of existing studies on influenza drug and vaccine development.…”

“…Designing a universal influenza vaccine that is sufficiently immunogenic to induce universal antibodies capable of neutralizing a broad range of influenza isolates is difficult partly because of the lack of highly conserved epitopes in the HA globular head region [16,23]. With the advances in antibody discovery-related technologies, a growing number of antibodies are being identified, and some of them target critical functional regions that are not highly sensitive to antigenic drifts in the HA domain [67,68].…”

“…The structural studies showed that the binding sites of the three antibodies belonged to the HA head domain in the same epitope that is ordinarily occluded on a prefusion structure and hidden in the trimeric HA head interface. With the introduction of non-native putative N-linked glycosylation sites, such occluded and highly conserved epitopes were exposed in the glycosylated HA molecules; such condition allowed for the broad (but not complete) antibody mAb 8H10 to recognize all of the identified H3 types and a representative H4 type [16,76]. The article proposed that hyperglycosylated HA could block some epitopes from exposure to occluded epitopes and elicit broadly protective responses.…”

“…Yu et al isolated mAb m826 as a novel epitope in the HA trimeric interface that exerted highly therapeutic effects on mice with a lethal challenge of H7N9 [15]. This interface was previously considered to be hidden but can be exposed according to the recently proposed HA "breathing" theory [16]. Consequently, panels of broadly neutralizing antibodies targeting these epitopes were identified [16][17][18].…”